Reduction method for substituted 5-methylene-thiazolidinediones

ABSTRACT

The present invention provides a method for making known pharmaceutical compounds. More particularly the present invention provides a new reduction method for making thiazolidinedione derivatives, particularly ciglitazone, pioglitazone, and englitazone. This reduction method comprises reacting a compound of the formula II with a cobalt ion, a ligand and a reducing agent to achieve a compound of the formula I. ##STR1##

FIELD OF INVENTION

This application is the national phase of international applicationPCT/US92/10329, filed 4 Dec. 1992, which is a continuation-in-part ofU.S. Ser. No. 07/811,103, filed 20 Dec. 1991, now abandoned.

The present invention provides a new method of making organic compounds.In particular, the present invention provides a new reduction method formaking certain pharmaceutically active compounds, such asthiazolidinedione derivatives, including pioglitazone, ciglitazone,englitazone and CS-045. These compounds are known for the treatment ofdiabetes and as insulin sensitizing agents.

BACKGROUND

Pioglitazone hydrochloride((±)-5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedionemonohydrochloride), a thiazolidinedione derivative, is currently underclinical evaluation and is expected to effectively ameliorate theabnormal glucose and lipid metabolism associated with NIDDM or obesity(cf. Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991)).

T. Sohda, et al., J. Med. Chem. 35:2617-2626 (1992), disclosesadditional thiazolidinedione derivatives as potent hypoglycemic andhypolipidemic agents. including5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione,which had the most potent activity, more than 100 times that ofpioglitazone.

Another thiazolidine derivative under-going clinical studies as ahypoglycemic agent is englitazone sodium,5-([3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl[methyl]-2,4-thiazolidinedione sodium salt) (cf. D. A.Clark et al., J. Med. Chem., 34:319-325 (1991)).

Ciglitazone ((±)-5- [4-[(1-methylcyclohexyl)methoxy]benzyl]-2,4-thiazolidinedione) ischaracteristic of a new class of thiazolidine antidiabetic agents whichlower blood glucose in animal models of noninsulin diabetes mellitus(NIDDM), while actually reducing circulating concentrations of insulin.This is believed to be accomplished by improving the responsiveness ofthe peripheral tissues to insulin. See, e.g., Chang, et al, Diabetes32:830-838 (September 1983).

CS-045 is an antidiabetic, thiazolidinedione derivative. Its activityand preparation are described in Drugs Fut. 1991, 16(9).

Also, thiazolidine derivatives useful for the treatment of diabetes aredescribed in U.S. Pat. Nos. 4,287,200; 4,687,777; and 4,572,9 12. Theireffect on insulin resistance are described, e.g. in, Chang, et al,Diabetes 32:839-845 (1983) and Chang, et al. Diabetes 32:830-838 (1983).

The preparation of these thiazolidinedione derivatives, especiallypioglitazone hydrochloride, includes the reduction of an intermediatepreviously performed by a troublesome high pressure hydrogenation on apalladium on carbon catalyst. What is needed in the art is an easier,more efficient method for perfoming this reduction.

INFORMATION DISCLOSURE

Y. Momose et at., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al.,Japan. Patent 139182 (1988); Chem. Abstr., 109:6504h (1988); disclosethe process for making thiazolidinedione-derivatives, includingpioglitazone, using hydrogen on a palladium on carbon catalyst.

D. A. Clark et at., J. Med. Chem., 34:319-325 (1991) discloses theprocess for making substituted dihydrobenzopyran and dihydrobenzofuranthiazolidine-2,4-diones, including englitazone, using hydrogen on apalladium on carbon catalyst.

Drugs Fut. 1991, 16(9) discloses the multistep process, via carbonalkylation, for the preparation of the thiazolidinedione CS-045.

The following references disclose cobalt catalyzed reductions: U.Leutenegger et al., Angew. Chem. Int. Ed., 28:60 (1989) discloses theenantioselective reduction of α,β-unsaturated carboxylates with sodiumborohydride and catalytic amounts of chiral cobalt semicorrin complexes;and M. N. Ricroch and A. Gaudemer, J. Organometal. Chem., 67:119 (1974)discloses (pyridinato) cobaloxime, chloro (pyridinato) cobaloxime andvitamin B ₁₂ catalyzing the hydrogenation of α,β-unsaturated esters byhydrogen or sodium borohydride.

J. O. Oshy, et al., J.A.C.S. 108:67-72 (1986), discloses cobalt(II)-mediated sodium borohydride and lithium aluminum hydridereductions, which do not involve the use of ligands.

SUMMARY OF THE INVENTION

The present invention particularly provides:

A process for preparing a compound of the formula I (refer to FormulaChart below)

wherein X₁ is an organic residue; which comprises:

(a) reacting a compound of the formula II with a cobalt ion, a ligandand a reducing agent;

This process wherein the temperature is -20° to 45° C. and wherein asuitable solvent is used;

This process wherein X₁ is the residue of an antidiabetic compound;

This process wherein X₁ is

(a) aryl, or

(b) Het;

wherein aryl is phenyl or naphthyl substituted by zero to three of thefollowing:

(a) C₁ -C₃ alkyl,

(b) hydroxy,

(c) C₁ -C₃ alkoxy,

(d) halo,

(e) amino,

(f) mono- or di-C₁ -C₃ alkylamino,

(g) nitro,

(h) mercapto,

(i) C₁ -C₃ alkylthio,

(j) C₁ -C₃ alkylsulfinyl,

(k) C₁ -C₃ alkylsulfonyl,

(l) --NH--C₁ -C₃ alkylsulfonyl,

(m) --NC₁ -C₃ alkyl-C₁ -C₃ alkylsulfonyl,

(n) SO₃ H,

(o) SO₂ NH₂,

(p) --CH₂ NH₂,

(q) --A₁ --(CH₂)_(n) -Het,

(r) --A₁ --(CH₂)_(n) -(C₁ -C₆ alkyl substituted cyclohexyl), or

(s) --A₁ --(CH₂)_(n) - cyclohexyl;

wherein A₁ is

(a) O, or

(b) S;

wherein Het is a 5- or 6-membered saturated or unsaturated ringcontaining from one to three heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a phenylring; which heterocycle ring is substituted by zero to three of thefollowing:

(a) C₁ -C₆ alkyl,

(b) hydroxy,

(c) hydroxy (C₁ -C₅ alkyl),

(d) halogen,

(e) amino,

(f) amino (C₁ -C₅ alkyl),

(g) nitro,

(h) mercapto,

(i) mercapto (C₁ -C₅ alkyl),

(j) --SO₃ H,

(k) --SO₂ NH₂,

(l) --O--C₁ -C₅ alkyl,

(m) --(CH₂)_(n) - aryl, or

(n) --(CH₂)_(n) - cyclohexyl;

wherein n is zero to five, inclusive;

This process wherein X_(l) is the moiety of formula III (refer toFormula Chart below) wherein

R₁ is hydrogen;

wherein

R₂ is

(a) --O--(CH₂)-(5-ethyl-2-pyridyl),

(b) --O--CH₂ -(1-methylcyclohexyl),

(c) the moiety of formula IV (refer to Formula Chart below); or

wherein R₁ and R₂ taken together are the moiety of formula V (refer toFormula Chart below);

This process wherein X_(l) is the moiety of formula VI (refer to FormulaChart below);

This process wherein the cobalt ion is in the form of

(a) cobaltous chloride,

(b) cobaltous diacetate, or

(c) cobaltic chloride;

wherein the ligand is

(a) dimethylglyoxime,

(b) 2,2'-bipyridyl, or

(c) 1,10-phenanthroline;

wherein the reducing agent is

(a) sodium borohydride,

(b) lithium borohydride,

(c) potassium borohydride,

(d) tetraalkylammonium borohydride, or

(e) zinc borohydride;

This process wherein the cobalt ion is in the form of cobaltouschloride, the ligand is dimethylglyoxime and the reducing agent issodium borohydride;

This process wherein the solvent is

(a) methanol,

(b) ethanol,

(c) i-propanol,

(d) acetone,

(e) dimethylformamide, or

(f) tetrahydrofuran;

provided, however, that if (d), (e) or (f) is the solvent, (a), (b), (c)or water must also be present;

This process wherein the temperature is 5° to 20° C. and the solvent iswater and tetrahydrofuran;

This process wherein X₁ is the moiety of formula VI (refer to FormulaChart below);

This process which further comprises:

(b) reacting the compound of the formula I (refer to Formula Chartbelow) with hydrochloric acid to obtain a compound of the formula VII(refer to Formula Chart below.

Previously, the preparation of thiazolidinedione derivatives includedthe reduction of an intermediate done as a troublesome high pressurehydrogenation on a palladium on carbon catalyst. Surprisingly andunexpectedly, the present invention provides a new, more efficientmethod for performing this reduction which uses a cobaltouschloride/bidentate ligand/sodium borohydride catalyst system and thevariations thereof as described below. This new reduction method isfaster and easier and results in improved yield of the desired product.It is also more convenient to scale into production equipment since nohigh pressure apparatus is required.

By "organic residue" is meant the residue of an organic compound thatwould be compatible with the reaction conditions of the process of thepresent invention. Preferably, such a residue will be one that does notreact with the reactants of the process of the present invention so thatonly the double bond at the 5-position of the thiazolidinedione ringwill be reduced. The reactants of the present invention include a cobaltion, a ligand and a reducing agent. Such an organic residue would bereadily determined by one of ordinary skill in the chemical arts.

By "residue of an antidiabetic compound" is meant the organic moietythat is attached to the 5-position of a thiazolidinedione derivative,which derivative has antidiabetic activity, such as those described inY. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al.,Japan. Patent 139182 (1988); Chem. Abstr., 109:6504h (1988); D. A. Clarket al., J. Med. Chem., 34:319-325 (1991); U.S. Pat. Nos. 4,287,200;4,687,777; and 4,572,912; Drugs Fut 1991, 16(9); and J. Med. Chem.35:2617-2626 (1992). The description of the preparation of theintermediates of these compounds of formula II is expressly incorporatedby reference herein. The process of the present invention is preferablyapplicable to the commercially important thiazolidinediones,pioglitazone hydrochloride (the compound of formula VII in the FormulaChart,) ciglitazone (the compound of formula X in the Formula Chart),englitazone (the compound of formula XX in the Formula Chart), CS-045(the compound of formula XXX in the Formula Chart) and the recentlydisclosed thiazolidinedione of formula XL. All of the intermediates offormula II may readily be prepared by procedures analogous to thosedescribed above by one of ordinary skill in the art.

By "aryl" is meant phenyl or naphthyl substituted by zero to three ofthe following: C₁ -C₃ alkyl, hydroxy, C₁ -C₃ alkoxy, halo, amino, mono-or di-C₁ -C₃ alkylamino, nitro, mercapto, C₁ -C₃ alkylthio, C₁ -C₃alkylsulfinyl, C₁ -C₃ alkylsulfonyl, --NH--C₁ -C₃ alkylsulfonyl, --NC₁-C₃ alkyl-C₁ -C₃ alkylsulfonyl, SO₃ H, SO₂ NH₂, --CH₂ NH₂,--A₁-(CH₂)_(n) -Het, --A₁ --(CH₂)_(n) --(C₁ -C₆ alkyl substitutedcyclohexyl), or --A₁ --(CH₂)_(n) - cyclohexyl; wherein A₁ is O, or S;

By "Het" is meant a 5- or 6-membered saturated or unsaturated ringcontaining from one to three heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a phenylring; which heterocycle ring is substituted by zero to three of thefollowing: C₁ -C₆ alkyl, hydroxy, hydroxy (C₁ -C₅ alkyl), halogen,amino, amino (C₁ -C₅ alkyl), nitro, mercapto, mercapto (C₁ -C₅ alkyl),--SO₃ H, --SO₂ NH₂, --O--C₁ -C₅ alkyl, --(CH₂)_(n) - aryl, or--(CH₂)_(n) -cyclohexyl; wherein n is zero to five, inclusive.

The reaction temperature range for the process of the present inventionis -20° C. to +45° C. The preferred range is +5° to +20° C. +15° C. ismost preferred.

Solvents that will work in the process of the present invention includemethanol, ethanol, i-propanol, acetone, dimethylformamide (DME) andtetrahydrofuran (THF); with the proviso that if acetone, DMFF or THF areused then a proton source, such as an alcohol, like the ones mentionedabove, or water must also be present. The amount of such proton sourcerequired would typically be ≧1eq., but would be readily apparent to oneof ordinary skill in the art. Water and tetrahydrofuran are a preferredsolvent combination.

Cobalt is the preferred metal ion (Co⁺² or Co⁺³). Sources of cobaltinclude CoCl₂ (cobaltous chloride) and Co(OAc)₂ (cobaltous diacetate) orCoCl₃ (cobaltic chloride).

By "ligand" is meant a complexing agent for a metal ion. In addition todimethylglyoxime, which is the preferred ligand, other ligands that maybe used are 2, 2'-bipyridyl and 1,10-phenanthroline, which should beused in at least a 1:1 mole ratio with the cobalt ion. Most preferred isthe ligand to cobalt ratio of 50:1.

Sodium borohydride (NaBH₄) is the preferred reducing agent, but otherborohydrides, such as lithium borohydride, potassium borohydride,tetraalkylammonium borohydride or zinc borohydride may be used.

By "halo" is meant the halogens: fluorine, chlorine and bormine.

CHART A

Chart A illustrates the preparation of pioglitazone hydrochloride usingthe new reduction step of the present invention.

The compound of formula A-1 is prepared as described in Y. Momose etal., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent139182 (1988); and Chem. Abstr., 109:6504h (1988); which are expresslyincorporated by reference herein.

The compound of formula A-1 is reduced to the compound of formula A-2using a cobaltous chloride/bidentate ligand/sodium borohydride catalystsystem. These reactants may be varied, as described above, by one ofordinary skill in the art.

The compound of formula A-2 is converted to the hydrochloride salt offormula A-3 by procedures readily known and available to one of ordinaryskill in the art, including the use of concentrated hydrochloric acid.

Below are detailed examples illustrating this new reduction method. Theprocedures of Example 3 are most preferred.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is seen more fully by the examples below.

EXAMPLE 1 Reduction Step in the Preparation of PioglitazoneHydrochloride (Formula A-3) Refer to Chart A.

Part A

A slurry of 3.544 g of the compound of formula A-1 in 45 ml of water iscooled to 3° C. and 0.51 ml of 50% sodium hydroxide is added. Theresulting solution is then treated with 22 mg of dimethylglyoxime, andthen 1.0 g of powdered blue indicating silica gel (containing about 0.7wt % CoCl₂), 432 mg of sodium borohydride and 5.0 ml ofdimethylformamide (DMF) are added in that order. A thin black slurryresults. The reaction mixture is stirred at about 17° C. for 25 hours atwhich time high pressure liquid chromatography (LC) indicates noremaining starting material. The silica gel is removed by filtration andthe flask and solids are rinsed with a little water. The combinedflitrate and rinse are treated with a solution of 1.90 ml acetic acid in14ml of water in order to precipitate the product. After stirring for 2hours at room temperature, the solids are collected by filtration,rinsed with three-14 ml portions of water and vacuum dried at 60° C.overnight to provide 3.20 g of crude product of formula A-2.

Part B

This product is slurried with 3.2 g of magnesol in 70 nil of ethylacetate for 2 hours at 70° C. This slurry is transferred to a soxletextraction thimble aid the solids are extracted with hot ethyl acetate(100 ml) for 5 days. The volume of the product slurry is adjusted to 70ml by distillation and then the temperature is lowered to 50° C. and 2.2ml of concentrated hydrochloric acid is added. The resulting slurry ofthe hydrochloric acid (HC 1) salt is stirred at 50° C. for 1 hour andthen cooled to 0° C. The solids are collected, rinsed with three-8 mlportions of room temperature ethyl acetate and dried at 60° C. overnightto give 3.025 g of the title product.

EXAMPLE 2 Reduction Step in the Preparation of PioglitazoneHydrochloride (Formula A-3) Refer to Chart A.

Part A

To a 100 ml 3-necked round bottomed flask, equipped with mechanicalstirrer, is charged 1.772 g of the compound of formula A-1, 25 ml ofwater, 6.0 ml of tetrahydrofuran, and 2.0 ml of 1.0N sodium hydroxide.The mixture is stiffed at 25° C. for 10 min. and cooled to 15° C. To thecooled mixture is added 0.05-0.50 ml of catalyst solution, prepared bydissolving 0.232 g of dimethylglyoxime and 0.012 g of cobaltous chloride•6 H₂ O in 5.0 ml of dimethylformamide, and then a solution of 0.378 gof sodium borohydride and 0.5 ml of 1.0N sodium hydroxide diluted with3.5 ml of water is added at a rate of 0.1 ml/min. The reaction isstirred at 15° C. for 3 hours and then 2.6 ml of acetone is added toquench any remaining sodium borohydfide. After stirring for 0.5 hours,the solution is extracted with three 15 ml portions of ethyl acetate,and then it is acidified by the dropwise addition of 2.3 ml of glacialacetic acid diluted with 5.0 ml of water. Upon acidification, theproduct precipitates as white solids. The slurry is cooled to 0° C. andstirred for 0.5 hours prior to filtration. The collected product iswashed with three 15 ml portions of water and dried at 45° C. undervacuum. The yield of crude product of formula A-2 is 1.583 g.

Part B

The crude product of formula A-2 is converted to the hydrochloride salttitle product by the method described in Example 1, Part B.

EXAMPLE 3 Reduction Step in the Preparation of Piogliazone Hydrochloride(Formula A-3) Refer to Chart A.

Part A

A slurry of 5.0 g of the compound of formula A-1 in 15 ml of water, 9 mlof tetrahydrofuran and 9.5 ml of 1N sodium hydroxide is treated with asolution of 42 mg of cobalt (II) chloride •H₂ O in 4 ml of 1:1 aqueoustetrahydrofuran. The temperature is adjusted to 15° C. and a solution of667 mg of sodium borohydride in 15 ml of water containing 1.8 ml of 1Nsodium hydroxide is added dropwise while maintaining the temperature at15° C. to 18° C. The reaction mixture is quenched with 5.3 ml of acetoneand then extracted with ethyl acetate as described in Example 2. Theaqueous layer containing crude product of formula A-2 is acidified to pH6.5 using 9 ml of 20% aqueous acetic acid. The resulting slurry istreated with 25 ml of ethyl acetate and is stirred at 70° C. for 2hours. After cooling the slurry to 15° C., the solids are collected,washed first with water and then with methanol followed by drying at 65°C. The yield of the product of formula A-2 is 4.75 g.

Part B

A 5.00 g sample of the above solids is slurried at room temperature in30 ml of methanol and then treated with 1.0 equivalent of conc.hydrochloric acid in 13 ml of methanol. The slurry is stiffed at 24° C.until all of the solids dissolved (2 hours). The solution isconcentrated by vacuum distillation to 20 ml. The solvent changes overto ethyl acelate by displacement vacuum distillation. The desiredhydrochloride salt precipitates during this solvent exchange. The slurryis cooled to 2° C. and the solids are collected by vacuum filtration,washed with cold ethyl acetate and dried in the vacuum oven at 60° C.The pioglitazone hydrochloride salt weighed 5.06 g and showed 97.7%quality by LC analysis. ##STR2##

I claim:
 1. A process for preparing a compound of the formula IwhereinX₁ is the moiety of formula III ##STR3## wherein R₁ is hydrogen;whereinR₂ is(a) --O--(CH₂)₂ -(5-ethyl-2-pyridyl), (b) --O--CH₂-(1-methylcylohexyl), (c) the moiety of formula IV; or ##STR4## whereinR₁ and R₂ taken together are the moiety of formula V ##STR5## whichcomprises: (a) reacting a compound of the formula II ##STR6## with acobalt ion, a ligand and a reducing agent in a suitable solvent. whereinthe cobalt ion is in the form of (a) cobaltous chloride, (b) cobaltousdiacetate, or (c) cobaltic chloride; wherein the ligand is(a)dimethylglyoxime, (b) 2,2'-bipyridyl, or (c) 1,10-phenanthroline;wherein the reducing agent is(a) sodium borohydride, lithiumborohydride, potassium borohydride, (d) tetraalkylammonium borohydride,or zinc borohydride.
 2. The process of claim 1 wherein the temperatureis -20° to 45° C.
 3. The process of claim 2 wherein the temperature is5° C. to 20° C.
 4. The process of claim 1 wherein the cobalt ion is inthe form of cobaltous chloride, the ligand is dimethylglyoxime and thereducing agent is sodium borohydride.
 5. The process of claim 1whereinthe solvent is(a) methanol, (b) ethanol, (c) i-propanol, (d) acetone,(e) dimethylformamide, or (f) tetrahydrofuran; provided, however, thatif (d), (e) or (f) is the solvent, (a), (b), (c) or water must also bepresent.
 6. The process of claim 5 wherein the solvent is water andtetrahydrofuran.
 7. The process of claim 4 wherein X₁ is ##STR7##
 8. Theprocess of claim 7 which further comprises:(b) reacting the compound ofthe formula I with hydrochloric acid to obtain a compound of the formulaVII ##STR8##